Abstract
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3+ regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. Here, we show that induction of human IFN-γ−IL-17A−Foxp3+CD4+ T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Consistently, the expression of IGF1R and TGFBR1 on circulating naive CD4+ T cells is reduced in patients with MS. Thus, our study shows that exosomal let-7i regulates MS pathogenesis by blocking the IGF1R/TGFBR1 pathway.
Highlights
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system
Exosomes are secreted from various cell types, circulate in the body, and alter the function of the recipient cells via delivery of the exosomal Micro RNAs (miRNA)
We evaluated if the relationship might exist between the frequency of the IFN-γ−IL-17A−Foxp3+CD4+ Treg cells after culture (Fig. 1d) and the amount of miRNAs in the exosomes added to the culture (Fig. 2d)
Summary
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. Foxp3+ regulatory T (Treg) cells are reduced in frequency and dysfunctional in patients with MS, but the underlying mechanisms of this deficiency are unclear. We show that induction of human IFN-γ−IL-17A−Foxp3+CD4+ T cells is inhibited in the presence of circulating exosomes from patients with MS. The exosomal miRNA profile of patients with MS differs from that of healthy controls, and let-7i, which is markedly increased in patients with MS, suppresses induction of Treg cells by targeting insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Several miRNAs are more abundant in the MS-exosome than in exosomes from healthy donors Among those upregulated in patients with MS, let-7i can suppress Treg cell induction by inhibiting the expression of insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1). Our findings imply that altered miRNA expression in MS-exosome may contribute to the pathogenesis by disrupting the homeostasis of Treg cells
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